Introduction: Femoropopliteal (FP) Tosaka class III in-stent restenosis (ISR) lesions remain a significant clinical problem and optimal revascularization management including the use of drug-coated balloon (DCB) and debulking devices has the potential to improve the outcomes for these patients. Aim: To compare clinical outcomes of debulking plus DCB with DCB alone in Tosaka III FP-ISR treatment in a Chinese population. Material and methods: This was a single-center retrospective study of patients who underwent endovascular interventions of debulking plus DCB or DCB alone for Tosaka III FP-ISR lesions. One-year primary patency was the main outcome. Other outcome measures are 12-month freedom from clinical-driven target lesion revascularization (f-CD-TLR), technical success rate, and periprocedural complications. Results: A total of 80 patients with Tosaka III FP-ISR were included; 39 were treated with debulking plus DCB, among whom 22 were treated with laser atherectomy (LA) plus DCB and 17 were treated with rotational atherectomy (RA) plus DCB. 41 were treated with DCB alone. 12-month primary patency was significantly different between the debulking + DCB and DCB groups (87.2% vs. 65.9%, p = 0.039). in the subgroup comparison, no significant difference was found between the LA + DCB and RA + DCB groups (86.4% vs. 88.2%, p = 0.842). There were also no significant differences in the group and subgroup comparison of 12-month f-CD-TLR, technical success rate, and periprocedural complications. Conclusions: In this small preliminary experience, combined treatment with debulking and DCB angioplasty is correlated with better outcomes in 1-year primary patency for Tosaka III FP-ISR lesions.